The aim of this project is to critically examine fluid fluxes in circulatory shock states to determine if, as is widely accepted, sustained net fluid filtration is an unportant determinant of irreversibility. Additionally, conditions and/or substances liberated in shock states which promote edema formation will be systematically studied to more precisely determine their role in fluid movement in shock. Hypoxia and histamine-like substances will be studied during this project period. Specifically, the major aim is to determine why, despite severe hypoxemia and high levels of circulating histamine, only evidence for net extravascular reabsorption rather than fluid filtration was found in severe hemorrhagic and endotoxin shock states in skeletal muscle. These data may also shed new light on the microcirculatory actions of histamine. It is interesting to note that although local intra-arterially administered histamine clearly promotes edema formation, systemically (intravenously) administered histamine not only fails to increase fluid filtration, but rather leads to extravascular fluid reabsorption. The mechanism of this unique route-dependent differential action of histamine has never been established. BIBLIOGRAPHIC REFERENCES: G.L. Miller, R.L. Kline, J.B. Scott, F.J. Haddy and G.J. Grega: Effects of ischemia on forelimb weight and lymph protein concentration. Proc. Soc. Exptl. Biol. Med. 149: 581-586, 1975. F.J. Haddy and G.J. Grega: Effects of bradykinin on skin lymph flow and protein concentration in the dog forelimb. Acta physiol. latin. 24, 469-474, 1975.